PROJECT SUMMARY/ABSTRACT The brain expresses several distinct types of internally generated sequences of neuronal activity independent of external sensory stimuli, and such temporally precise, self-organized sequences play a crucial role in information processing and memory formation/retrieval. In particular, the hippocampus generates two separate, well-defined forms of neuronal sequences: sharp-wave/ripple (SWR)-associated sequences which are observed during ?off-line? states such as rest or sleep, and theta-associated sequences which occur during ?on-line? states such as active exploration. Prior work has demonstrated a link between SWR sequences and working memory, long-term memory, and future planning, while theta sequences have been associated with decision-making and immediate future behaviors. However, little is known regarding how these two sequence types interact with experience or each other to facilitate mnemonic processes. Further, the circuit mechanisms which allow specific neuronal activity patterns to be expressed within internally generated sequences are largely unknown. The central objective of this study is to utilize ultra-high density, large-scale in vivo electrophysiology coupled with complex spatial navigational tasks to examine in depth these two forms of sequential activity to identify fundamental principles which underlie their generation, function, and relationship to each other. Supported by considerable preliminary data, we propose to pursue this objective through three specific aims: (1) To define the relationship between internally generated sequences and ongoing behavior during periods of memory formation vs. memory retrieval/use; (2) To determine the mechanisms underlying development, persistence, and function of internally generated sequences in sleep; (3) To identify how the patterns and weights of connectivity within the hippocampus contribute to the expression and propagation of internally generated sequences. Together, this study is expected to meaningfully advance our understanding of circuit-level brain function by revealing the fundamental principles which allow precise patterns of activity to be dynamically generated and propagated throughout the hippocampal network in support of learning.